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      Characterizing blood–brain barrier perturbations after exposure to human triglyceride‐rich lipoprotein lipolysis products using MRI in a rat model

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          Abstract

          Purpose

          Previous studies indicated hyperlipidemia may be a risk factor for Alzheimer's disease, but the contributions of postprandial triglyceride‐rich lipoprotein (TGRL) are not known. In this study, changes in blood–brain barrier diffusional transport following exposure to human TGRL lipolysis products were studied using MRI in a rat model.

          Methods

          Male Sprague‐Dawley rats (∼180–250 g) received an i.v. injection of lipoprotein lipase (LpL)‐hydrolyzed TGRL (n = 8, plasma concentration ≈ 150 mg human TGRL/dL). Controls received i.v. injection of either saline (n = 6) or LpL only (n = 6). The 1H longitudinal relaxation rate R 1 = 1/T 1 was measured over 18 min using a rapid‐acquired refocus‐echo (RARE) sequence after each of three injections of the contrast agent Gd‐DTPA. Patlak plots were generated for each pixel yielding blood‐to‐brain transfer coefficients, K i, chosen for best fit to impermeable, uni‐directional influx or bi‐directional flux models using the F‐test.

          Results

          Analysis from a 2‐mm slice, 2‐mm rostral to the bregma showed a 275% increase of mean K i during the first 20 min after infusion of human TGRL lipolysis product that differed significantly compared with saline and LpL controls. This difference disappeared by 40 min mark.

          Conclusion

          These results suggest human TGRL lipolysis products can lead to a transient increase in rat BBB permeability. Magn Reson Med 76:1246–1251, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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          Blood-brain barrier: structural components and function under physiologic and pathologic conditions.

          Yuri Persidsky, Servio H. Ramirez, James Haorah … (2006)
          The blood-brain barrier (BBB) is the specialized system of brain microvascular endothelial cells (BMVEC) that shields the brain from toxic substances in the blood, supplies brain tissues with nutrients, and filters harmful compounds from the brain back to the bloodstream. The close interaction between BMVEC and other components of the neurovascular unit (astrocytes, pericytes, neurons, and basement membrane) ensures proper function of the central nervous system (CNS). Transport across the BBB is strictly limited through both physical (tight junctions) and metabolic barriers (enzymes, diverse transport systems). A functional polarity exists between the luminal and abluminal membrane surfaces of the BMVEC. As a result of restricted permeability, the BBB is a limiting factor for the delivery of therapeutic agents into the CNS. BBB breakdown or alterations in transport systems play an important role in the pathogenesis of many CNS diseases (HIV-1 encephalitis, Alzheimer's disease, ischemia, tumors, multiple sclerosis, and Parkinson's disease). Proinflammatory substances and specific disease-associated proteins often mediate such BBB dysfunction. Despite seemingly diverse underlying causes of BBB dysfunction, common intracellular pathways emerge for the regulation of the BBB structural and functional integrity. Better understanding of tight junction regulation and factors affecting transport systems will allow the development of therapeutics to improve the BBB function in health and disease.
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            Waxholm Space atlas of the Sprague Dawley rat brain.

            Eszter Papp, Trygve B. Leergaard, Evan Calabrese … (2014)
            Three-dimensional digital brain atlases represent an important new generation of neuroinformatics tools for understanding complex brain anatomy, assigning location to experimental data, and planning of experiments. We have acquired a microscopic resolution isotropic MRI and DTI atlasing template for the Sprague Dawley rat brain with 39 μm isotropic voxels for the MRI volume and 78 μm isotropic voxels for the DTI. Building on this template, we have delineated 76 major anatomical structures in the brain. Delineation criteria are provided for each structure. We have applied a spatial reference system based on internal brain landmarks according to the Waxholm Space standard, previously developed for the mouse brain, and furthermore connected this spatial reference system to the widely used stereotaxic coordinate system by identifying cranial sutures and related stereotaxic landmarks in the template using contrast given by the active staining technique applied to the tissue. With the release of the present atlasing template and anatomical delineations, we provide a new tool for spatial orientation analysis of neuroanatomical location, and planning and guidance of experimental procedures in the rat brain. The use of Waxholm Space and related infrastructures will connect the atlas to interoperable resources and services for multi-level data integration and analysis across reference spaces.
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              Inflammatory mediators and modulation of blood-brain barrier permeability.

              N J Abbott (2000)
              1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.
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                Author and article information

                Contributors
                John C. Rutledge: jcrutledge@ucdavis.edu
                Journal
                Journal ID (nlm-ta): Magn Reson Med
                Journal ID (iso-abbrev): Magn Reson Med
                Journal ID (doi): 10.1002/(ISSN)1522-2594
                Journal ID (publisher-id): MRM
                Title: Magnetic Resonance in Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0740-3194
                ISSN (Electronic): 1522-2594
                Publication date (Electronic): 20 October 2015
                Publication date (Print): October 2016
                Volume: 76
                Issue: 4 ( doiID: 10.1002/mrm.v76.4 )
                Pages: 1246-1251
                Affiliations
                [ 1 ] School of Medicine, Division of Cardiovascular MedicineUniversity of California Davis CaliforniaUSA
                [ 2 ] School of Medicine, Department of Physiology and Membrane BiologyUniversity of California Davis CaliforniaUSA
                [ 3 ] NMR Facility and Biomedical Engineering Graduate GroupUniversity of California Davis CaliforniaUSA
                Author notes
                [*] [* ]Correspondence to: John C. Rutledge, M.D., Division of Cardiology, 5404 Genome and Biomedical Sciences Facility, 451 East Health Sciences Drive, University of California, Davis, CA 95616. E‐mail: jcrutledge@ 123456ucdavis.edu
                Article
                Publisher ID: MRM25985
                DOI: 10.1002/mrm.25985
                PMC ID: 4838551
                PubMed ID: 26485349
                SO-VID: 5d27eb27-3ded-485e-aec9-d845fc95feec
                Copyright © © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 04 June 2015
                Date revision received : 11 August 2015
                Date accepted : 21 August 2015
                Page count
                Figures: 3, Tables: 1, Pages: 6, Words: 4015
                Funding
                Funded by: NSF
                Award ID: OSTI 97‐24412
                Funded by: NIH
                Award ID: R01‐AG039094
                Funded by: Richard A. and Nora Eccles Harrison Endowed Chair in Diabetes Research
                Categories
                Subject: Note
                Subject: Preclinical and Clinical Imaging—Note
                Custom metadata
                source-schema-version-number 2.0
                component-id mrm25985
                cover-date October 2016
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:06.10.2016

                ScienceOpen disciplines: Radiology & Imaging
                Keywords: hyperlipidemia,triglyceride‐rich lipoprotein,permeability,blood–brain barrier,gd‐dtpa
                Data availability:
                ScienceOpen disciplines: Radiology & Imaging
                Keywords: hyperlipidemia, triglyceride‐rich lipoprotein, permeability, blood–brain barrier, gd‐dtpa

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